On the retention of neurotensin in the ventral tegmental area (VTA) despite destruction of the main neurotensinergic afferents of the VTA--implications for the organization of forebrain projections to the VTA.

Neurotensin (NT) modulates ventral tegmental area (VTA) signaling in a manner relevant to psychostimulant drug actions, thus inviting evaluation of psychostimulant effects in conditions of reduced or absent VTA NT. However, in a preliminary study, NT immunoreactivity (-ir) in the VTA was unaffected following destruction of the main concentration of forebrain neurotensinergic VTA afferents in the lateral preoptic-rostral lateral hypothalamic continuum (LPH) and adjacent lateral part of the medial preoptic area (MPOA). This study attempted to determine what measures are necessary to obtain a significant reduction of VTA NT-ir. Large unilateral ibotenic acid lesions were made in several structures containing NTergic, VTA-projecting neurons, including the LPH-MPOA, nucleus accumbens, VTA itself and dorsal raphe. None of these was associated with substantial ipsilateral loss of NT-ir in the VTA, lateral hypothalamus or lateral habenula. Combinations of lesions, such as LPH-MPOA plus VTA and LPH-MPOA plus dorsal raphe, also failed to substantially reduce NT-ir in these structures. Transections of the medial forebrain bundle (mfb) likewise failed to produce a substantial loss of VTA NT-ir measured with immunohistochemistry and radioimmunoassay. Transections of the mfb were carried out in combination with infusions of retrograde and anterograde axonal tract-tracers, revealing that the routes taken by some forebrain NT-ir VTA afferents circumvent mfb transections. All of these results together are consistent with the hypothesis that the connectional organization of forebrain and brainstem, potentially in combination with limited adaptive synaptogenesis, renders the VTA relatively insensitive to moderate losses of neurotensinergic and, perhaps, other peptidergic afferents.